Tyrosine kinase inhibitor and application thereof

ABSTRACT

The invention discloses a compound with the general formula of (I), wherein, K is selected from: naphthene alkyl 
     
       
         
         
             
             
         
       
     
     and haloalkane alkyl 
     
       
         
         
             
             
         
       
     
     or N—R6. The invention also discloses a tyrosine kinase inhibitor containing the above compound and the application of the compound in preparing drugs for treating cancers. The tyrosine kinase inhibitor of the invention inhibits the bioactivity of multiple signal conduction kinases such as C-MET, VEGF, KDR, etc., it can effectively inhibit cell proliferation and has favorable therapeutic effects on various diseases such as cancer, it has significant therapeutic effects especially on lung cancer, gastric cancer, ovarian cancer, malignant glioma, etc., and it has a very broad application prospect.

FIELD OF THE INVENTION

The invention relates to the technical field of medicine, in particularto a tyrosine kinase inhibitor and the applications thereof.

BACKGROUND OF THE INVENTION

Protein kinase is a phosphotransferase that transfers the gammaphosphate ester group of adenosine triphosphate (ATP) to a specificamino acid residue, in order to achieve protein phosphorylation andthereby achieve its physiological and biochemical functions.

Protein kinase has an important function in information conduction.Abnormal protein kinase cannot perform normal signal transmission andmay cause pathological changes, such as protein kinases of tumor cellproliferation, cell death, inflammation, cardiovascular disease, etc.Protein kinase is mainly divided into two categories: protein tyrosinekinase (PTKs) and receptor tyrosine kinase (RTKs). ROS1/C-MET in the METprotein kinase is an important subline of RTPs, and it is also known ashHGFR and RON; ROS1/C-MET can play an important role in the growth andmetabolism of tumor initiating cells, and it is the target for clinicalresearches on multiple drugs.

Therefore, ROS1/C-MET kinase inhibitors, especially tyrosine kinaseinhibitors of micromolecular compounds, are urgently needed in the fieldof biomedical technology.

SUMMARY OF THE INVENTION

The technical problem to be solved for the invention is to provide atyrosine kinase inhibitor, the kinase inhibitor can inhibit the activityof multiple tyrosine kinases involved in signal conduction, such asC-MET, VEGF, KDR, RON, KIT, PDGF, FGF, SRC, etc., and it can effectivelyinhibit the proliferation of tumor cells to get better therapeuticeffect on cancers in clinic.

In order to solve the above technical problem, the invention isimplemented by the following technical schemes:

On one aspect of the invention, it provides a compound with the generalformula of (I)

or its pharmaceutically acceptable salts thereof, wherein,

K is selected from the following groups: naphthene alkyl

haloalkane alkyl

or N—R6; b and d are 1, 2, 3 or 4; E and G are one of hydrogen, halogen,hydroxy, alkoxy, ketone, sulfydryl and alkyl sulfydryl, but E and G canbe hydrogen at the same time; R6 is one of hydrogen, inferior haloalkanealkyl, inferior halogenated naphthene alkyl, inferior alkyl and inferiornaphthene alkyl;

R1, R2, R3, R4 and R5 are one or several of hydrogen, halogen, inferiorhaloalkane alkyl, inferior halogenated naphthene alkyl, inferior alkyl,inferior naphthene alkyl, hydroxy, inferior alkoxy, inferiorcycloalkoxy, inferior alkylene and inferior alkyne, respectively;

X is one of C—R, C—(CN) and N, and R is one of hydrogen, halogen,inferior haloalkane alkyl, interior halogenated naphthene alkyl,inferior alkyl, inferior naphthene alkyl, hydroxy, inferior alkoxy,inferior cycloalkoxy, inferior alkylene and inferior alkyne;

Y is one of O, S and N—R6 or is null, and M is O or null;

a and c represent 0, 1, 2 or 3, respectively; e is 1 or 2.

Preferably, at least one of E and G is haloge F.

Preferably, Y is O or null.

Preferably, the compounds with the general formula of (I) comprise thecompounds in the following specific structures:

On another aspect of the invention, it also provides a pharmaceuticalcomposition, and the composition comprises the above compound of sateand effective dose and a pharmaceutically acceptable carrier.

The above acceptable carrier is nontoxic and can be used for auxiliaryapplication without adverse effect on the therapeutic effect of thecompound. Such carrier can be any commonly available solid excipient,liquid excipient, semi-solid excipient or gas excipient in aerosolcomposition for the technicians in this field. Solid drug excipientsinclude starch, cellulose, talc, glucose, lactose, sucrose, gelatin,malt, rice, flour, chalk, silica gel, magnesium stearate, sodiumstearate, glyceryl stearyl ester, sodium chloride, anhydrous skim milk,etc. Liquid and semi-solid excipients can be selected from glycerin,propylene glycol, water, ethanol and various oils, including the oiloriginated from petroleum, animal and plant or synthetic oil, such aspeanut oil, soybean oil, mineral oil, sesame oil, etc. Preferable liquidcarriers, especially those used for injectable solutions, include,water, saline, glucose aqueous solution and glycol. In addition, otheradjuvants such as flavoring agent, sweetening agent, etc. can also beadded in the composition.

The compound of the invention can be applied in the therapeuticeffective dose, it can be applied either orally or for the whole body(such as transcutaneously, nasal inhalation or suppository) orparenterally (such as intramuscularly, intravenously or subcutaneously).Oral administration is preferred, and it can be adjusted according tothe severity of disease.

The actual application amount (i.e., active ingredient) for the compoundof the invention depends on multiple factors, such as the severity ofdisease to be treated, the age and relative health level of the treatedsubject, the efficacy of the used compound, way and form of application,and other factors.

Various dosage forms of the medicinal composition of the invention canbe prepared in accordance with the conventional methods in the field ofpharmacy. For example, mix the compound with one or several carriers,and then prepared it into the desired dosage form, such as tablets,pills, capsules, semi solid, powder, slow release formulation, solution,suspension, compounding solvent, aerosol, etc.

On another aspect of the invention, it also provides a tyrosine kinaseinhibitor containing the above compound.

The tyrosine kinase comprises the kinases of C-MET, VEGF, KDR, RON, KIT,PDGF, FGF and SRC.

On another aspect of the invention, it also provides the application ofthe above compound in preparing drugs for treating cancers.

Tyrosine kinase is a target with obvious effect for anti-tumor drugs,whereas the compound of the invention has significant activity ininhibiting tyrosine kinase, experiments have confirmed that thesecompounds have inhibitory effect on the proliferation of various cancercells, and thus the compound of the invention is applicable for treatingvarious cancers. Especially, it has better therapeutic effects on lungcancer, gastric cancer, ovarian cancer, colon cancer and malignantglioma.

On another aspect of the invention, it also provides the application ofthe above compound in preparing drugs for treating inflammations.

The compound of the invention and multiple signal conduction kinasessuch as C-MET, VEGF, KDR, RON, KIT, PDGF, FGF, SRC, etc. all havefavorable bioactivity and are associated with multiple signal conductionpathways, and thus they have therapeutic effects on various diseases,such as cancer, inflammation, lymphedema, diabetes mellitus, etc.

The tyrosine kinase inhibitor of the invention can inhibit thebioactivity of multiple signal conduction kinases such as C-MET, VEGF,KDR, etc., it can effectively inhibit cell proliferation and hasfavorable therapeutic effects on various diseases such as cancer, it hassignificant therapeutic effects especially on lung cancer, gastriccancer, ovarian cancer, malignant glioma, etc., and it has a very broadapplication prospect.

BRIEF DESCRIPTION OF DRAWINGS

The invention will be further explained in details by combining with thedrawings and embodiments.

FIG. 1 is the fitted curve for the inhabitation on the proliferation ofhuman lung adenocarcinoma cells HCC78 in Embodiment 10 of the invention;

FIG. 2 is the fitted curve for the inhabitation on the proliferation ofhuman malignant glioma cells U87MG in Embodiment 10 of the invention;

FIG. 3 is the fitted curve for the inhabitation on the proliferation ofhuman gastric cancer cells MKN-45 in Embodiment 10 of the invention;

FIG. 4 is the fitted curve for the inhabitation on the proliferation ofhuman lung adenocarcinoma cells HCC78 in Embodiment 10 of the invention;

FIG. 5 is the fitted curve for the inhabitation on the proliferation ofhuman lung ovarian cancer cells SK-OV-3 in Embodiment 10 of theinvention;

FIG. 6 is the fitted curve for the inhabitation on the proliferation ofhuman colon cancer cells HCT116 in Embodiment 10 of the invention;

FIG. 7 is the fitted curve for the inhabitation on the proliferation ofhuman lung adenocarcinoma cells A549 in Embodiment 10 of the invention.

DETAILED DESCRIPTION OF THE INVENTION Embodiment 1 Synthesis of TyrosineKinase Inhibitor Compound 24

Wherein, compound A is

Including the following steps:

Step 1, dissolve 1.3 g, 7 mmol of Compound 19 in 50 ml of methalnol,Compound 19 is trans-diethyl 1,2-cyclopropanedicarboxylate, then add 1Nof 1 mol/L NaOH solution into the above solution, and stir at roomtemperature to stay overnight; dilute the overnight reaction solutionwith water, and then extract it with ethyl acetate; wash the organicphase obtained by extraction with saturated saline solution, addanhydrous sodium sulfate after washing for drying, and then concentrateand dry it by distillation; after drying by distillation, purify theabove organic phase concentrated and dried by distillation using columnchromatography on silica gel, and obtain 1 g of yellow grease 20 with ayield of 77%; Compound 20 is trans-ethyl 1,2-cyclopropanedicarboxylate,and the specific reaction formula is as below:

Step 2, dissolve 1 g, 6 mmol of Compound 20 in 30 mL ofdimethylformamide (DMF), then add 4.6 g, 12 mmol of polypeptidecondensing agent (HATU) and 3 mL of triethylamine into the abovesolution, then add 0.6 g, 6 mmol of morpholine after stirring at roomtemperature for 0.5 h, and stir at room temperature to stay overnight;dilute the overnight reaction solution with water, and then extract itwith ethyl acetate; wash the organic phase obtained by extraction withsaturated saline solution, add anhydrous sodium sulfate after washingfor drying, and then concentrate and dry it by distillation; afterdrying by distillation, purify the above organic phase concentrated anddried by distillation using column chromatography on silica gel, andobtain 1 g of colorless liquid with a yield of 77% as Compound 21;Compound 21 is (1s,2s)-2-morpholine-4-carbonyl) cyclopropane ethyl, andthe specific reaction formula is as below:

Step 3, dissolve 1 g, 4 mmol of Compound 21 in 30 mL of THF, add 1N of 1mol/L lithium aluminium hydride (LAH) solution wider ice bath, and stirat room temperature for 2 h; then filter the uniformly stirred reactionsolution after quenching with sodium sulfate decahydrate; wash theorganic phase obtained by extraction with saturated saline solution, addanhydrous sodium sulfate after washing for drying, and then concentrateand dry it by distillation; perform purification by columnchromatography on silica gel, and purify the above organic phaseconcentrated and dried by distillation using column chromatography onsilica gel, and obtain 0.5 g of colorless liquid as Compound 22 with ayield of 66%; Compound 22 is (1s,2s)-2-morpholine methyl) cyclopropylmethanol, and the specific reaction formula is as below:

Step 4, dissolve 0.3 g, 1.7 mmol of Compound 22 in 30 mL ofdichloromethane, then add 0.3 g, 3.4 mmol of N-methyl pyrrole and 0.3 g,1.7 mmol of paratoluensulfonyl chloride into the above solution, andstir at room temperature to stay overnight; dilute the overnightreaction solution with water, and then extract it with ethyl acetate;wash the organic phase obtained by extraction with saturated salinesolution, add anhydrous sodium sulfate after washing for drying, andthen concentrate and dry it by distillation; purify the above organicphase concentrated and dried by distillation using column chromatographyon silica gel, and obtain 0.1 g of white solid with a yield of 18% asCompound 23; Compound 23 is (1s,2s)-2-morpholine methyl)cyclopropyl-p-methyl benzenesulfonate, and the specific reaction formulais as below:

Step 5, dissolve 0.1 g, 0.2 mmol of compound A (compound A isN-p-fluorophenyl-N-3-fluoro-4-(6-methoxyl-7-hydroxyquinoline-4-)phenoxyl cyclopropyl-1,1-dimethyl formamide) and 0.1 g, 0.3 mmol ofCompound 23 in 10 mL of acetonitrile, then add 0.2 g. 0.5 mmol of cesiumcarbonate into the above solution, and stir by backflow to stayovernight; dilute the overnight reaction solution with water, and thenextract it with ethyl acetate; wash the organic phase obtained byextraction with saturated saline solution, add anhydrous sodium sulfateafter washing for drying, and then concentrate and dry it bydistillation; after drying by distillation, purify the above organicphase concentrated and dried by distillation using the reversepreparation method, and obtain 0.01 g of yellow solid with a yield of 8%as Compound 24; Compound 24 isN-p-fluorophenyl-N-3-fluoro-4-[6-methoxyl-7-(1S,2S)-2-morpholinomethylcyclopropyl methoxyquinoline-4-] phenoxyl cyclopropyl-1,1-dimethylformamide, and the specific reaction formula is as below:

Embodiment 2 Synthesis of Tyrosine Kinase Inhibitor Compound 5

Including the following steps:

Step 1, dissolve 1 g, 5.2 mmol of Compound 1 (Compound 1 is3-(phenylmethoxy ethyl) cyclobutyl-1-ketone) and 0.46 g, 5.2 mmol ofmorpholine in 30 mL of dichloroethane, then add 3.3 g, 15.6 mmol ofacetate sodium borohydride and 1 drop of acetic acid into the abovesolution, and stir by backflow to stay overnight; dilute the overnightreaction solution with water, and then extract it with ethyl acetate;wash the organic phase obtained by extraction with saturated salinesolution, add anhydrous sodium sulfate after washing for drying, andthen concentrate and dry it by distillation;purify the above organicphase concentrated and dried by distillation using column chromatographyon silica gel, and obtain 1 g of colorless liquid with a yield of 73% asCompound 2; Compound 2 is (3-morpholine-cyclobutyl-1-) methyl benzylether, and the specific reaction formula is as below:

Step 2, dissolve 1 g, 3.8 mmol of Compound 2 into 30 mL of methalnol,then add 0.1 g of palladium black and 2 mL of methanoic acid into theabove solution, and stir by backflow to stay overnight; dilute theovernight reaction solution with water, and then extract it with ethylacetate; wash the organic phase obtained by extraction with saturatedsaline solution, add anhydrous sodium sulfate after washing for drying,and then concentrate and dry it by distillation; purity the aboveorganic phase concentrated and dried by distillation using columnchromatography on silica gel, and obtain 0.3 g of colorless liquid witha yield of 46% as Compound 3; Compound 3 is 3-morpholine-cyclobutylmethalnol, and the specific reaction formula is as below:

Step 3, dissolve 0.3 g, 1.7 mmol of Compound 3 in 30 mL ofdichloromethane, add 0.3 g, 3.4 mmol of N-methyl pyrrole and 0.3 g, 1.7mmol of paratoluensulfonyl chloride into the above solution, and stir atroom temperature to stay overnight; dilute the overnight reactionsolution with water, and then extract it with ethyl acetate; wash theorganic phase obtained by extraction with saturated saline solution, addanhydrous sodium sulfate after washing for drying, and then concentrateand dry it by distillation; purify the above organic phase concentratedand dried by distillation using column chromatography on silica gel, andobtain 0.2 g of white solid with a yield of 35% as Compound 4; Compound4 is N-p-fluorophenyl-N-3-fluoro-4-(6-methoxyl-7-hydroxyquinoline-4-)phenoxyl cyclopropyl-1,1-dimethyl formamide, and the specific reactionformula is as below:

Step 4, dissolve 0.1 g. 0.2 mmol of compound A (compound A isN-p-fluorophenyl-N-3-fluoro-4-(6-methoxyl-7-hydroxyquinoline-4-)phenoxyl cyclopropyl-1,1-dimethyl formamide) and 0.1 g, 0.3 mmol ofCompound 4 in 10 mL of acetonitrile, add 0.2 g, 0.5 mmol of cesiumcarbonate, and stir by backflow to stay overnight; dilute the overnightreaction solution with water, and then extract it with ethyl acetate;wash the organic phase obtained by extraction with saturated salinesolution, add anhydrous sodium sulfate after washing for drying, andthen concentrate and dry it by distillation; after drying bydistillation, purify the above organic phase concentrated and dried bydistillation using the reverse preparation method, and obtain 0.02 g ofyellow solid with a yield of 16% as Compound 5; Compound 5 isN-p-fluorophenyl-N-3-fluoro-4-[6-methoxyl-7-(3-morpholine-cyclobutyl)methoxyquinoline-4-] phenoxyl cyclopropyl-1,1-dimethyl formamide), andthe specific reaction formula is as below:

Embodiment 3 Synthesis of Tyrosine Kinase Inhibitor Compound 10

Including the following steps:

Step 1, dissolve 1 g, 5.2 mmol of Compound 6 (Compound 6 is 3-benzyloxycyclobutyl-1-ketone) and 0.46 g, 5.2 mmol of morpholine in 30 mL ofdichloroethane, add 3.3 g, 15.6 mmol of acetate sodium borohydride and 1drop of acetic acid into the above solution, and stir at roomtemperature to stay overnight; dilute the overnight reaction solutionwith water, and then extract it with ethyl acetate; wash the organicphase obtained by extraction with saturated saline solution, addanhydrous sodium sulfate after washing for drying, and then concentrateand dry it by distillation; purify the above organic phase concentratedand dried by distillation using column chromatography on silica gel, andobtain 1.1 g of colorless liquid with a yield of 80% as Compound 7;Compound 7 is 3-morpholine-cyclobutyl benzyl ether, and the specificreaction formula is as below:

Step 2, dissolve 1 g, 3.8 mmol of Compound 7 in 30 mL of methalnol, add0.1 g of palladium black and 2 mL of methanoic acid into the abovesolution, and stir by backflow to stay overnight; dilute the overnightreaction solution with water, and then extract it with ethyl acetate;wash the organic phase obtained by extraction with saturated salinesolution, add anhydrous sodium sulfate after washing for drying, andthen concentrate and dry it by distillation; purify the above organicphase concentrated and dried by distillation using column chromatographyon silica gel, and obtain 0.3 g of colorless liquid with a yield of 46%as Compound 8; Compound 8 is 3-morpholine-cyclobutanol, and the specificreaction formula is as below:

Step 3, dissolve 0.3 g, 1.7 mmol of Compound 8 in 30 mL ofdichloromethane, add 0.3 g, 3.4 mmol of N-methyl pyrrole and 0.3 g, 1.7mmol of paratoluensulfonyl chloride into the above solution, and stir atroom temperature to stay overnight; dilute the overnight reactionsolution with water, and then extract it with ethyl acetate; wash theorganic phase obtained by extraction with saturated saline solution, addanhydrous sodium sulfate after washing for drying, and then concentrateand dry it by distillation; purify the above organic phase concentratedand dried by distillation using column chromatography on silica gel, andobtain 0.1 g of white solid with a yield of 18% as Compound 9; Compound9 is p-toluenesulfonic acid (3-morpholine-cyclobutyl) ether, and thespecific reaction formula is as below:

Step 4, dissolve 0.1 g, 0.2 mmol of Compound A in 10 mL of dioxane,compound A isN-p-fluorophenyl-N-3-fluoro-4-(6-methoxyl-7-hydroxyquinoline-4-)phenoxyl cyclopropyl-1,1-dimethyl formamide, add 0.02 g, 0.2 mmol ofpotassium tert-butoxide into the above solution, add 0.1 g, 0.3 mmol ofCompound 9 after stirring at room temperature for 0.5 h, and stir at 50°C. to stay overnight; dilute the overnight reaction solution with water,and then extract it with ethyl acetate; wash the organic phase obtainedby extraction with saturated saline solution, add anhydrous sodiumsulfate after washing for drying, and then concentrate and dry it bydistillation; after drying by distillation, purify the above organicphase concentrated and dried by distillation using the reversepreparation method, and obtain 0.1 g of yellow solid with a yield of 8%as Compound 10; Compound 10 isN-p-fluorophenyl-N-3-fluoro-4-[6-methoxyl-7-(3-morpholine-cyclobutyl)aminoquinoline-4-]phenoxyl cyclopropyl-1,1-dimethyl formamide, and thespecific reaction formula is as below:

Embodiment 4 Synthesis of Tyrosine Kinase Inhibitor Compound 38

Wherein, compound B has the structural formula below:

Including the following steps:

Step 1, dissolve 1 g, 5.2 mmol of Compound 34 and 0.46 g, 5.2 mmol ofmorpholine in 30 mL of dichloroethane, Compound 34 is 3-benzyloxycyclobutyl-1-ketone, add 3.3 g, 15.6 mmol of acetate sodium borohydrideand 1 drop of acetic acid into the above solution, and stir at roomtemperature to stay overnight; dilute the overnight reaction solutionwith water, and then extract it with ethyl acetate; wash the organicphase obtained by extraction with saturated saline solution, addanhydrous sodium sulfate after washing for drying, and then concentrateand dry it by distillation; purify the above organic phase concentratedand dried by distillation using column chromatography on silica gel, andobtain 1.1 g of colorless liquid with a yield of 80% as Compound 35;Compound 35 is 3-morpholine-cyclobutyl benzyl ether, and the specificreaction formula is as below:

Step 2, dissolve 1 g, 3.8 mmol of Compound 35 in 30 mL of methalnol, add0.1 g of palladium black and 2 mL of methanoic acid into the abovesolution, and stir by backflow to stay overnight; dilute the overnightreaction solution with water, and then extract it with ethyl acetate;wash the organic phase obtained by extraction with saturated salinesolution, add anhydrous sodium sulfate after washing for drying, andthen concentrate and dry it by distillation; purify the above organicphase concentrated and dried by distillation using column chromatographyon silica gel, and obtain 0.3 g of colorless liquid with a yield of 46%as Compound 36; Compound 36 is 3-morpholine-cyclobutanol, and thespecific reaction formula is as below:

Step 3, dissolve 0.3 g, 1.7 mmol of Compound 36 in 30 mL ofdichloromethane, add 0.3 g. 3.4 mmol of N-methyl pyrrole and 0.3 g, 1.7mmol of paratoluensulfonyl chloride, and stir at room temperature tostay overnight; dilute the overnight reaction solution with water, andthen extract it with ethyl acetate; wash the organic phase obtained byextraction with saturated saline solution, add anhydrous sodium sulfateafter washing for drying, and then concentrate and dry it bydistillation; purify the above organic phase concentrated and dried bydistillation using column chromatography on silica gel, and obtain 0.1 gof white solid with a yield of 18% as Compound 37; Compound 37 is3-morpholine-cyclobutyl benzyl ether, and the specific reaction formulais as below:

Step 4, dissolve 0.1 g, 0.2 mmol of Compound B in 10 mL of dioxane,compound B isN-p-fluorophenyl-N-3-fluoro-4-(6-methoxyl-7-hydroxyquinoline-4-)benzyloxy cyclobutyl-1, 1-dimethyl formamide, add 0.02 g, 0.2 mmol ofpotassium tert-butoxide, add 0.1 g, 0.3 mmol of Compound 33 afterstirring at room temperature for 0.5 h, Compound 33 is p-tuluenesulfonicacid (3-morpholine-cyclobutyl) ester, and stir at 50° C. to stayovernight; dilute the overnight reaction solution with water, and thenextract it with ethyl acetate; wash the organic phase obtained byextraction with saturated saline solution, add anhydrous sodium sulfateafter washing for drying, and then concentrate and dry it bydistillation; after drying by distillation, purify the above organicphase concentrated and dried by distillation using the reversepreparation method, and obtain 0.01 g of yellow solid with a yield of 8%as Compound 38; Compound 38 isN-p-fluorophenyl-N-3-fluoro-4-[6-methoxyl-7-(3-morpholine-cyclobutyl)aminoquinoline-4-] benzyloxy cyclobutyl-1,1-dimethyl formamide, and thespecific reaction formula is as below:

Embodiment 5 Synthesis of Tyrosine Kinase Inhibitor Compound 15

Including the following steps:

Step 1, dissolve 2 g, 12 mmol of Compound 11 and 1 g, 12 mmol ofmorpholine in 30 mL of DMF, Compound 11 is 2,2-dimethyl fluoromalonate,and stir at 100° C. to stay overnight; dilute the overnight reactionsolution with water, and then extract it with ethyl acetate; wash theorganic phase obtained by extraction with saturated saline solution, addanhydrous sodium sulfate after washing for drying, and then concentrateand dry it by distillation; purify the above organic phase concentratedand dried by distillation using column chromatography on silica gel, andobtain 1.5 g of colorless liquid with a yield of 57% as Compound 12;Compound 12 is 2,2-difluoro-3-morpholine-3-oxopropionate, and thespecific reaction formula is as below:

Step 2, dissolve 1.5 g, 7 mmol of Compound 12 in 30 mL oftetrahydronfuran (THF), add 1 mol/L of 28 mL, 28 mmol LAH under icebath, and stir at room temperature for 2 h; then filter the overnightreaction solution after quenching with sodium sulfate decahydrate; washthe organic phase obtained by extraction with saturated saline solution,add anhydrous sodium sulfate after washing for drying, and thenconcentrate and dry it by distillation; purify the above organic phaseconcentrated and dried by distillation using column chromatography onsilica gel, and obtain 0.5 g of colorless liquid with a yield of 41% asCompound 13; Compound 13 is 2,2-difluoro-3-morpholine-1-propyl alcohol,and the specific reaction formula is as below:

Step 3, dissolve 0.3 g, 1.7 mmol of Compound 13 in 30 mL ofdichloromethane, add 0.3 g, 3.4 mmol of N-methyl pyrrole and 0.3 g, 1.7mmol of paratoluensulfonyl chloride into the above solution, and stir atroom temperature to stay overnight; dilute the overnight reactionsolution with water, and then extract it with ethyl acetate; wash theorganic phase obtained by extraction with saturated saline solution, addanhydrous sodium sulfate after washing for drying, and then concentrateand dry it by distillation; purify the above organic phase concentratedand dried by distillation using column chromatography on silica gel, andobtain 0.1 g of white solid with a yield of 18% as Compound 14; Compound14 is p-tuluenesulfonic acid (2,2-difluoro-3-morpholine-1-) propylester, and the specific reaction formula is as below:

Step 4, dissolve 0.1 g, 0.2 mmol of Compound A and 0.1 g, 0.3 mmol ofCompound 14 in 10 mL of acetonitrile, compound A isN-p-fluorophenyl-N-3-fluoro-4-(6-methoxyl-7-hydroxyquinoline-4-)phenoxyl cyclopropyl-1,1-dimethyl formamide, add 0.2 g, 0.5 mmol ofcesium carbonate into the above solution, and stir by backflow to stayovernight; dilute the overnight reaction solution with water, and thenextract it with ethyl acetate; wash the organic phase obtained byextraction with saturated saline solution, add anhydrous sodium sulfateafter washing for drying, and then concentrate and dry it bydistillation; after drying by distillation, purify the above organicphase concentrated and dried by distillation using the reversepreparation method, and obtain 0.01 g of yellow solid with a yield of 8%as Compound 15; Compound 15 isN-p-fluorophenyl-N-3-fluoro-4-[6-methoxyl-7-(2,2-difluoro-3-morpholine-1-)propoxy quinoline-4-]phenoxyl cyclopropyl-1,1-dimethyl formamide, andthe specific reaction formula is as below:

Embodiment 6 Synthesis of Tyrosine Kinase Inhibitor Compound 27

compound A is

Including the following steps:

Step 1, dissolve 0.1 g, 1 mmol of Compound 25 and 0.18 g, 1 mmol of1,2-dibromoethane in 10 mL of acetonitrile, Compound 25 isN-aminomorpholine, add 0.65 g, 2 mmol of cesium carbonate into the abovesolution, and stir at room temperature to stay overnight; dilute theovernight reaction solution with water, and then extract it with ethylacetate; wash the organic phase obtained by extraction with saturatedsaline solution, add anhydrous sodium sulfate after washing for drying,and then concentrate and dry it by distillation;after drying bydistillation, purify the above organic phase concentrated and dried bydistillation using column chromatography on silica gel, and obtain 0.1 gof colorless liquid with a yield of 50% as Compound 26; Compound 26 isN-(2-bromomethyl) morpholine-4-amine, and the specific reaction formulais as below:

Step 2, dissolve 0.1 g. 0.2 mmol of Compound A and 0.06 g, 0.3 mmol ofCompound 26 in 10 mL of acetonitrile, compound A isN-p-fluorophenyl-N-3-fluoro4-(6-methoxyl-7-hydroxyquinoline-4-) phenoxylcyclopropyl-1,1-dimethyl formamide, add 0.2 g, 0.5 mmol of cesiumcarbonate into the above solution, and stir by backflow to stayovernight; dilute the overnight reaction solution with water, and thenextract it with ethyl acetate; wash the organic phase obtained byextraction with saturated saline solution, add anhydrous sodium sulfateafter washing for drying, and then concentrate and dry it bydistillation; after drying by distillation, purify the above organicphase concentrated and dried by distillation using the reversepreparation method, and obtain 0.01 g of yellow solid with a yield of 8%as Compound 27; Compound 27 isN-p-fluorophenyl-N-3-fluoro-4-[6-methoxyl-7-(morpholine-4-amine)ethoxyquinoline-4-]phenoxyl cyclopropyl-1,1-dimethyl formamide, and thespecific reaction formula is as below:

Embodiment 7 Synthesis of Tyrosine Kinase Inhibitor Compound 30

Including the following steps:

Step 1, dissolve 0.1 g, 1 mmol of Compound 28 and 0.18 g, 1 mmol of1,2-dibromoethane in 10 mL of acetonitrile, Compound 28 is4-aminoquinoline-3-ketone, add 0.65 g, 2 mmol of cesium carbonate intothe above solution, and stir at room temperature to stay overnight;dilute the overnight reaction solution with water, and then extract itwith ethyl acetate; wash the organic phase obtained by extraction withsaturated saline solution, add anhydrous sodium sulfate after washingfor drying, and then concentrate and dry it by distillation;after dryingby distillation, purify the above organic phase concentrated and driedby distillation using column chromatography on silica gel, and obtain0.1 g of colorless liquid with a yield of 50% as Compound 29; Compound29 is (2-bromoethylamine) morpholine-3-ketone, and the specific reactionformula is as below:

Step 2, dissolve 0.1 g, 0.2 mmol of Compound A and 0.06 g, 0.3 mmol ofCompound 29 in 10 mL of acetonitrile, compound A isN-p-fluorophenyl-N-3-fluoro4-(6-methoxyl-7-hydroxyquinoline-4-) phenoxylcyclopropyl-1,1-dimethyl formamide, add 0.2 g, 0.5 mmol of cesiumcarbonate into the above solution, and stir by backflow to stayovernight; dilute the overnight reaction solution with water, and thenextract it with ethyl acetate; wash the organic phase obtained byextraction with saturated saline solution, add anhydrous sodium sulfateafter washing for drying, and then concentrate and dry it bydistillation;after drying by distillation, purify the above organicphase concentrated and dried by distillation using the reversepreparation method, and obtain 0.012 g of yellow solid with a yield of9% as Compound 30, Compound 30 isN-p-fluorophenyl-N-3-fluoro-4-[6-methoxyl-7-(3-oxomorpholine amine)ethoxyquinoline-4-] phenoxyl cyclopropyl-1,1-dimethyl formamide, and thespecific reaction formula is as below:

Embodiment 8 Synthesis of Tyrosine Kinase Inhibitor Compound 33

Including the following steps:

Step 1, dissolve 0.1 g, 0.7 mmol of Compound 31 and 0.12 g, 0.7 mmol of1,2-dibromoethane in 10 mL of acetonitrile, Compound 31 is 3-morpholineazetidine, add 0.65 g, 2 mmol of cesium carbonate into the abovesolution, and stir at room temperature to stay overnight; dilute theovernight reaction solution with water, and then extract it with ethylacetate; wash the organic phase obtained by extraction with saturatedsaline solution, add anhydrous sodium sulfate after washing for drying,and then concentrate and dry it by distillation; purify the aboveorganic phase concentrated and dried by distillation using columnchromatography on silica gel, and obtain 0.1 g of colorless liquid witha yield of 50% as compound 32; Compound 32 is bromomethylazetidinemorpholine, and the specific reaction formula is as below:

Step 2, dissolve 0.1 g, 0.2 mmol of Compound A and 0.06 g, 0.24 mmol ofCompound 32 in 10 mL of acetonitrile, compound A isN-p-fluorophenyl-N-3-fluoro-4-(6-methoxyl-7-hydroxyquinoline-4-)phenoxyl cyclopropyl-1,1-dimethyl formamide, add 0.2 g, 0.5 mmol ofcesium carbonate into the above solution, and stir by backflow to stayovernight; dilute the overnight reaction solution with water, and thenextract it with ethyl acetate; wash the organic phase obtained byextraction with saturated saline solution, add anhydrous sodium sulfateafter washing for drying, and then concentrate and dry it bydistillation;after drying by distillation, purify the above organicphase concentrated and dried by distillation using the reversepreparation method, and obtain 0.09 g of yellow solid with a yield of 8%as Compound 33; Compound 33 isN-p-fluorophenyl-N-3-fluoro-4-[6-methoxyl-7-(morpholine-3-azetidine-1-)ethoxyquinoline-4-]phenoxyl cyclopropyl-1, 1-dimethyl formamide, and the specific reactionformula is as below:

Embodiment 9 Detection of the Inhibitory Activities of Tyrosine Kinases

The compounds in the above Embodiment are used for detecting andscreening the inhibitory activities of C-MET and KDR kinase.

1. Methods

(1) Add 4 μL of prepared kinase buffer solution or 4 μL of kinasesolution (100% inhibition control) in a 384-hole plate; add 2 μL of thecompound or 2 μL of buffer not containing the compound (0% inhibitioncontrol) into the holes; set 2 repetitive holes for all the samples orcontrol above.

(2) Incubate at 25° C. for 5 min;

(3) Add 2 μL of ATP/substrate/MgCl₂/MnCl₂/SEB/DTT mixed solution intothe holes;

(4) Centrifugated at 1000 rpm for 1 min, and incubate by vibration at30° C. for 30 min;

(5) Add 8 μL of XL-665/antibody mixed solution into the holes;

(6) Incubate at 25° C. for 1 h;

(7) Read the signals at 665 nm and 620 nm on PHERAstar FS;

(8) Analyze the data according to the instructions of the kit, andperform the fitting calculation of IC50 using GraphPad Prism5.

Ratio=665 nm/620 nm

${{Inhibition}\mspace{14mu} {rate}\mspace{14mu} {of}\mspace{14mu} {samples}\mspace{14mu} \%} = {\left( \frac{{Ratio}_{sample} - {Ratio}_{negative}}{{Ratio}_{positive} - {Ratio}_{negative}} \right) \times 100}$

2. Experimental Results

The detection results of the detected compounds and reference compoundare summarized as shown in Table 1 and Table 2, wherein, the controlcompound is the existing C-MET kinase inhibitor Foretinib (with thestructural formula below). The chemical structural formula of For-Oxideand For-Methyl are as below, respectively.

TABLE 1 Inhibitory activities of the Compounds on C-MET IC50 95Confidence Curve Compound No. cMet IC50 (nM) Interval (nM) R² Foretinib7.491 5.829 to 9.627 0.9884 For-Oxide 2.911 2.204 to 3.844 0.9850For-Methyl 162.7 107.8 to 245.5 0.9697 Compound 10 17.04 12.35 to 23.510.9814 Compound 5 20.55 17.07 to 24.74 0.9815 Compound 15 6.641 4.713 to8.552 0.9672 Compound 24 25.21 20.21 to 29.92 0.9770 Compound 33 15.0111.23 to 18.58 0.9711 Reference Compound 2.751 1.841 to 4.139 0.9685SCR-1510 (experimental internal reference)

TABLE 2 Inhibitory activities of the Compounds on KDR IC50 95 ConfidenceCompound No. KDR IC50 (nM) Interval (nM) Curve R² Foretinib 14.83 11.33to 19.41 0.9741 For-Oxide 10.6 8.628 to 13.09 0.9836 Compound 10 64.1654.00 to 76.24 0.9881 Compound 5 39.93 32.27 to 49.41 0.9714 PositiveRef 6774 5424 to 8460 0.8963

It can be known from the data of Tables 1-2 that the compounds in theabove embodiments of the invention have inhibitory activities on thetyrosine kinases of C-MET, KDR, etc.

Embodiment 10 Test of Inhibition on the Proliferation of Tumor Cells

1. Methods

(1) Culture cells: Culture tumor cells (such as human lungadenocarcinoma cells HCC78, human malignant glioma cells U87MG, humangastric cancer cells MKN-45, human umbilical vein endothelial cellsHUVEC, human lung adenocarcinoma cells A549, etc.) in culture medium;culture conditions: 37° C., 5% CO₂.

(2) Inoculate cells: Take the cells at the exponential growth phase andin good state, add an appropriate amount of pancreatin for celldissociation, collect the cells for centrifugation, and discard thesupernatant. Resuspend the cells with the culture solution containingserum, then cound and inoculate the cell suspensions in a 96-hole plateat 3000/hole, 90 μL/hole. Transfer the culture plate into a constanttemperature CO₂ incubator, and culture under the conditions of 37° C.,5% CO₂ and saturated humidity for 24 h.

(3) Add the test compounds: 10 μL/hole, culture for 72 h, set 3 parallelholes for each group.

(4) Determine the results: After 72 h of action for the compounds, add10 μL/hole CCK8, incubate in the incubator for an appropriate time, andmeasure the absorbance at 450 nm,

2. Experimental Results

The detection results of the detected compounds are summarized as shownin Tables 3-6:

TABLE 3 Results of Inhibition on the Proliferation of Human LungAdenocarcinoma Cells HCC78 (see FIG. 1 for the corresponding fittedcurve) 95% Confidence Interval Compound No. HCC78 IC50 (μM) (μM)Foretinib 0.1886 0.1253 to 0.2839 For-Oxide 0.1182 0.06890 to 0.2030 For-Methyl >10 / Compound 10 0.1072 0.06939 to 0.1656  SCR-1510 1.7791.001 to 3.160

TABLE 4 Results of Inhibition on the Proliferation of Human MalignantGlioma Cells U87MG Human Gastric Cancer Cells MKN-45 and Human LungAdenocarcinoma Cells HCC78 (see FIG. 2~FIG. 4 for the correspondingfitted curves) U87MG MKN-45 IC50 95% Confidence Interval IC50 95%Confidence Interval Compound No. (μM) (μM) R² (μM) (μM) R² Foretinib1.646 1.255 to 2.160 0.9424 1.867 1.387 to 2.513 0.9328 Compound 101.595 1.226 to 2.074 0.9473 3.205 2.788 to 3.684 0.9751 Compound 5 1.1390.8225 to 1.576  0.9323 1.262 0.9934 to 1.602  0.9613 HCC78 IC50 95%Confidence Interval (μM) (μM) R² Foretinib 0.07480 0.03897 to 0.1435 0.8136 Compound 10 / / / Compound 5 0.04417 0.03120 to 0.06254 0.9471

TABLE 5 Results of Inhibition on the Proliferation of Human OvarianCancer Cells SK-OV-3(see FIG. 5 for the corresponding fitted curve)SK-OV-3 IC50 95% Confidence Interval Compound No. (μM) (μM) R² Foretinib17.23 11.85 to 25.04 0.7477 For-Oxide 11.6 8.971 to 15.01 0.8846For-Methyl No inhibition / / Compound 10 7.849 5.925 to 10.40 0.8928Compound 5 3.494 3.155 to 3.869 0.9645

TABLE 6 Results of Inhibition on the Proliferation of Human Colon CancerCells HCT116 and Human Lung Adenocarcinoma Cells A549 (see FIG. 6 andFIG. 7 for the corresponding fitted curves) HCT116 A549 IC50 95%Confidence Interval IC50 95% Confidence Interval (μM) (μM) R² (μM) (μM)R² Foretinib 2.065 1.542 to 2.763 0.9391 2.833 2.167 to 3.704 0.9287For-Oxide 3.103 2.242 to 4.295 0.9149 4.921 3.965 to 6.107 0.9051For-Methyl No inhibition / / No inhibition / / Compound 10 2.605 2.262to 3.001 0.9713 4.397 3.676 to 5.259 0.9372 Compound 5 1.655 1.163 to2.356 0.8922 1.605 2.350 to 3.477 0.9527

It can be known from the data of Tables 3-6 that the compounds of theinvention can effectively inhibit the proliferation of various cancercells, such as human lung adenocarcinoma cells, human gastric cancercells, human gastric colon cancer cells, human gastric ovarian cancercells, human malignant glioma cells, etc. by inhibiting the activitiesof tyrosine kinases of C-MET, KDR, etc., and they are especiallysuitable for treating cancers.

The above embodiments only express the modes of execution of theinvention, they are described more specifically and in details, but theycan't be understood as the limitation to the scope of the patent of theinvention. It shall be indicated that for the common technicians in thisfield, under the premise without separating from the idea of theinvention, several transformations and improvements can also beobtained, and all these belong to the protective range of the invention.Therefore, the protective range for the patent of the invention shall besubject to the claims attached.

1. A compound of formula of (I)

or a pharmaceutically acceptable salts thereof, wherein, K is selected from the following groups: naphthene alkyl

and haloalkane alkyl

or N—R6; b and d are 1, 2, 3 or 4; E and G are one of hydrogen, halogen, hydroxy, alkoxy, ketone, sulfydryl and alkyl sulfydryl, but E and G can be hydrogen at the same time; R6 is one of hydrogen, inferior haloalkane alkyl, inferior halogenated naphthene alkyl, inferior alkyl and inferior naphthene alkyl; R1, R2, R3, R4 and R5 are one or several of hydrogen, halogen, inferior haloalkane alkyl, inferior halogenated naphthene alkyl, inferior alkyl, inferior naphthene alkyl, hydroxy, inferior alkoxy, inferior cycloalkoxy, inferior alkylene and inferior alkyne, respectively; X is one of C—R, C—(CN) and N, and R is one of hydrogen, halogen, inferior haloalkane alkyl, inferior halogenated naphthene alkyl, inferior alkyl, inferior naphthene alkyl, hydroxy, inferior alkoxy, inferior cycloalkoxy, inferior alkylene and inferior alkyne; Y is one of O, S and N—R6 or is null, and M is O or null; a and c represent 0, 1, 2 or 3, respectively; e is 1 or
 2. 2. The compound according to claim 1, wherein at least one of said E and G is haloge F.
 3. The compound according to claim 1, wherein said Y is O or null.
 4. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 5. A pharmaceutical composition, wherein the composition comprises a safe and effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. 6.-12. (canceled)
 13. The compound of claim 1, wherein the compound inhibits a tyrosine kinase.
 14. The compound of claim 13, wherein the tyrosine kinase comprises the kinases of C-MET, VEGF, KDR, RON, KIT, PDGF, FGF and SRC.
 15. A method of treating cancers in a subject in need thereof, comprising administering to the subject the compound according to claim
 1. 16. A method according to claim 15, wherein the cancers comprise lung cancer, gastric cancer, ovarian cancer, colon cancer, pancreatic cancer, adenocarcinoma of esophagus, and malignant glioma.
 17. A method of treating inflammations in a subject in need thereof, comprising administering to the subject the compound according to claim
 1. 18. A method of treating cancers in a subject in need thereof, comprising administering to the subject the pharmaceutical composition according to claim
 5. 19. A method of treating inflammations in a subject in need thereof, comprising administering to the subject the pharmaceutical composition according to claim
 5. 20. A pharmaceutical composition, wherein the composition comprises a safe and effective amount of the compound of claim 4 and a pharmaceutically acceptable carrier.
 21. The compound of claim 4, wherein the compound inhibits a tyrosine kinase.
 22. The compound of claim 21, wherein the tyrosine kinase comprises the kinases of C-MET, VEGF, KDR, RON, KIT, PDGF, FGF and SRC.
 23. A method of treating cancers in a subject in need thereof, comprising administering to the subject the compound according to claim
 4. 24. A method according to claim 23, wherein the cancers comprise lung cancer, gastric cancer, ovarian cancer, colon cancer, pancreatic cancer, adenocarcinoma of esophagus, and malignant glioma.
 25. A method of treating inflammations in a subject in need thereof, comprising administering to the subject the compound according to claim
 4. 26. A method of treating cancers in a subject in need thereof, comprising administering to the subject the pharmaceutical composition according to claim
 20. 27. A method of treating inflammations in a subject in need thereof, comprising administering to the subject the pharmaceutical composition according to claim
 20. 